This invention relates to a series of substituted 1,1-dioxo[d]isothiazol-3-one compounds which are inhibitors of 5-lipoxygenase (5-LO) per se and as such are useful in the treatment or alleviation of inflammatory diseases or conditions, allergy and cardiovascular diseases in mammals wherein the inflammatory disease or condition includes but is not limited to asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, shock, atopic dermatitis, rheumatoid arthritis or osteoarthritis; and this invention also relates to pharmaceutical compositions useful therefor.
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of arachidonic acid metabolism is the release of esterified arachidonic acid and related unsaturated fatty acids from membrane phospholipids via the action of phospholipase. Free fatty acids are then metabolized either by cycloxygenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia, reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently, several review articles on lipoxygenase inhibitors have been reported. See, for example, H. Masamune and L. S. Melvin, Jr., in Annual Reports in Medicinal Chemistry, 24, 71-80 (Academic Press, 1989) and B. J. Fitzsimmons and J. Rokach in Leukotrienes and Lipoxygenases, 427-502 (Elsevier, 1989).